Pathogenesis and diagnosis of myeloma cast nephropathy (myeloma kidney)
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
- Nelson Leung, MD
Nelson Leung, MD
- Associate Professor of Medicine
- Mayo Clinic College of Medicine
- S Vincent Rajkumar, MD
S Vincent Rajkumar, MD
- Edward W. and Betty Knight Scripps Professor of Medicine
- Mayo Clinic
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- Robert A Kyle, MD
Robert A Kyle, MD
- Section Editor — Plasma Cell Disorders
- Professor of Medicine
- Mayo Medical School
The term myeloma kidney or myeloma cast nephropathy refers to a disorder in which monoclonal urinary immunoglobulin light chains (Bence Jones proteins) lead to acute or chronic renal failure [1-3]. (See "Types of renal disease in multiple myeloma".) By definition, the diagnosis of light chain cast nephropathy indicates the presence of multiple myeloma; in other words, it is considered a "myeloma-defining event" . Light chain cast nephropathy can occur as the first manifestation of myeloma or can develop later during the course of myeloma.
This topic provides a review of the pathogenesis and diagnosis of myeloma cast nephropathy. Overviews of the renal diseases associated with multiple myeloma and the therapy of acute renal failure (ARF) in multiple myeloma are discussed separately. (See "Types of renal disease in multiple myeloma" and "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases" and "Treatment of kidney disease in multiple myeloma".)
Cast nephropathy is caused by large amounts of monoclonal free light chains (MFLCs) produced in multiple myeloma . Light chains are freely filtered across the glomerulus and then largely reabsorbed by the proximal tubular cells. The normal rate of light chain excretion is <30 mg/day. However, reabsorptive capacity can be exceeded due to overproduction in multiple myeloma, resulting in an increase in light chain excretion that can range from 100 mg to >20 g/day.
The risk of cast nephropathy is directly related to the urinary free light chain (FLC) concentration and the type of light chains . In an analysis of 2592 patients enrolled in multicenter myeloma trials, kidney injury developed in up to 54 percent of patients who had a high concentration of urinary FLC (defined as >12 g/g creatinine), but in ≤2 percent of patients with no urinary light chains . The risk of renal failure was approximately 8 to 18 and 29 to 38 percent among those who had urinary light chains of 0 to 4 and 4 to 12 g/g, respectively. However, urinary FLC measurements are rarely used in clinical practice since the test is unreliable. The methods used to estimate MFLC are the serum free light chain (SFLC) assay and the 24-hour urine protein electrophoresis. (See 'Diagnosis' below and "Recognition of monoclonal proteins".)
Cast nephropathy is uncommon in patients with low (<1500 mg/L) SFLC concentrations [8,9].
- DeFronzo RA, Cooke CR, Wright JR, Humphrey RL. Renal function in patients with multiple myeloma. Medicine (Baltimore) 1978; 57:151.
- Sanders PW. Pathogenesis and treatment of myeloma kidney. J Lab Clin Med 1994; 124:484.
- Heher EC, Rennke HG, Laubach JP, Richardson PG. Kidney disease and multiple myeloma. Clin J Am Soc Nephrol 2013; 8:2007.
- Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.
- Leung N, Behrens J. Current approach to diagnosis and management of acute renal failure in myeloma patients. Adv Chronic Kidney Dis 2012; 19:297.
- Ying WZ, Sanders PW. Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am J Pathol 2001; 158:1859.
- Drayson M, Begum G, Basu S, et al. Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials. Blood 2006; 108:2013.
- Hutchison CA, Cockwell P, Stringer S, et al. Early reduction of serum-free light chains associates with renal recovery in myeloma kidney. J Am Soc Nephrol 2011; 22:1129.
- Leung N, Gertz MA, Zeldenrust SR, et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 2008; 73:1282.
- Sanders PW, Booker BB. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992; 89:630.
- Huang ZQ, Sanders PW. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest 1997; 99:732.
- Pirani CL, Silva F, D'Agati V, et al. Renal lesions in plasma cell dyscrasias: ultrastructural observations. Am J Kidney Dis 1987; 10:208.
- Sanders PW, Booker BB, Bishop JB, Cheung HC. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990; 85:570.
- Myatt EA, Westholm FA, Weiss DT, et al. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci U S A 1994; 91:3034.
- Smolens P, Barnes JL, Kreisberg R. Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins. J Lab Clin Med 1987; 110:460.
- Holland MD, Galla JH, Sanders PW, Luke RG. Effect of urinary pH and diatrizoate on Bence Jones protein nephrotoxicity in the rat. Kidney Int 1985; 27:46.
- Morgan C Jr, Hammack WJ. Intravenous urography in multiple myeloma. N Engl J Med 1966; 275:77.
- Sakhuja V, Jha V, Varma S, et al. Renal involvement in multiple myeloma: a 10-year study. Ren Fail 2000; 22:465.
- Magee C, Vella JP, Tormey WP, Walshe JJ. Multiple myeloma and renal failure: one center's experience. Ren Fail 1998; 20:597.
- Sanders PW, Herrera GA, Chen A, et al. Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo. J Clin Invest 1988; 82:2086.
- Decourt C, Rocca A, Bridoux F, et al. Mutational analysis in murine models for myeloma-associated Fanconi's syndrome or cast myeloma nephropathy. Blood 1999; 94:3559.
- Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991; 324:1845.
- Kyle RA, Greipp PR. "Idiopathic" Bence Jones proteinuria: long-term follow-up in seven patients. N Engl J Med 1982; 306:564.
- Ying WZ, Allen CE, Curtis LM, et al. Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. J Clin Invest 2012; 122:1777.
- Ying WZ, Wang PX, Aaron KJ, et al. Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism. Blood 2011; 117:1301.
- Fattori E, Della Rocca C, Costa P, et al. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 1994; 83:2570.
- Sengul S, Zwizinski C, Simon EE, et al. Endocytosis of light chains induces cytokines through activation of NF-kappaB in human proximal tubule cells. Kidney Int 2002; 62:1977.
- Sengul S, Zwizinski C, Batuman V. Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. Am J Physiol Renal Physiol 2003; 284:F1245.
- Arimura A, Li M, Batuman V. Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. Blood 2006; 107:661.
- Sanders PW, Herrera GA, Lott RL, Galla JH. Morphologic alterations of the proximal tubules in light chain-related renal disease. Kidney Int 1988; 33:881.
- Leboulleux M, Lelongt B, Mougenot B, et al. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48:72.
- Lajoie G, Leung R, Bargman JM. Clinical, biochemical, and pathological features in a patient with plasma cell dyscrasia and Fanconi syndrome. Ultrastruct Pathol 2000; 24:221.
- Winearls CG. Acute myeloma kidney. Kidney Int 1995; 48:1347.
- Bladé J, Fernández-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998; 158:1889.
- Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 2001; 12:1482.
- Leung N, Gertz M, Kyle RA, et al. Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases. Clin J Am Soc Nephrol 2012; 7:1964.
- Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21.
- Ma CX, Lacy MQ, Rompala JF, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood 2004; 104:40.
- Nowrousian MR, Brandhorst D, Sammet C, et al. Serum free light chain analysis and urine immunofixation electrophoresis in patients with multiple myeloma. Clin Cancer Res 2005; 11:8706.
- Abadie JM, van Hoeven KH, Wells JM. Are renal reference intervals required when screening for plasma cell disorders with serum free light chains and serum protein electrophoresis? Am J Clin Pathol 2009; 131:166.
- Hutchison CA, Harding S, Hewins P, et al. Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3:1684.
- Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002; 48:1437.
- Vermeersch P, Van Hoovels L, Delforge M, et al. Diagnostic performance of serum free light chain measurement in patients suspected of a monoclonal B-cell disorder. Br J Haematol 2008; 143:496.
- Bochtler T, Hegenbart U, Heiss C, et al. Evaluation of the serum-free light chain test in untreated patients with AL amyloidosis. Haematologica 2008; 93:459.
- Buxbaum JN, Chuba JV, Hellman GC, et al. Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis. Ann Intern Med 1990; 112:455.
- Hill GS, Morel-Maroger L, Méry JP, et al. Renal lesions in multiple myeloma: their relationship to associated protein abnormalities. Am J Kidney Dis 1983; 2:423.
- Herrera GA. The kidney in plasma cell dyscrasias: a current view and a look at the future. Contrib Nephrol 2007; 153:1.
- Burke JR Jr, Flis R, Lasker N, Simenhoff M. Malignant lymphoma with "myeloma kidney" acute renal failure. Am J Med 1976; 60:1055.
- Isaac J, Herrera GA. Cast nephropathy in a case of Waldenström's macroglobulinemia. Nephron 2002; 91:512.
- Soffer O, Nassar VH, Campbell WG Jr, Bourke E. Light chain cast nephropathy and acute renal failure associated with rifampin therapy. Renal disease akin to myeloma kidney. Am J Med 1987; 82:1052.
- Cast nephropathy
- Tubular injury
- CLINICAL MANIFESTATIONS
- Serum free light chain assay
- Urine 24-hour protein quantitation and electrophoresis
- Serum protein electrophoresis and immunofixation
- Differential diagnosis
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS